IL23A (interleukin 23, alpha subunit p19)

2010-05-01   Norimitsu Inoue 

Department of Molecular Genetics, Osaka Medical Center for Cancer, Cardiovascular Diseases, Osaka, Osaka 537-8511, Japan

Identity

HGNC
LOCATION
12q13.3
LOCUSID
ALIAS
IL-23,IL-23A,IL23P19,P19,SGRF

DNA/RNA

Atlas Image
IL23A gene. The IL23A gene spans a region of 1531 bp composed of 4 exons [untranslated region (UTR), light blue; coding region, dark blue] with 328 bp, 99 bp, 147 bp and 467 bp in length, and 3 introns (brown) with 219 bp, 166 bp and 105 bp in length.

Description

4 exons.

Transcription

The transcript is 1041 bp, with a 166 bp 5 untranslated region (UTR), a 570 bp coding sequence, and a 305 bp 3 UTR.

Pseudogene

No pseudogene.

Proteins

Note

The IL23A protein (IL-23p19 subunit) is covalently linked to a p40 subunit (IL12B, IL-12p40), which is shared with IL-12, to form IL-23 (Oppmann et al., 2000). The IL23A protein requires IL12B for secretion. The receptor for IL-23 is formed by the association of a specific IL-23 receptor (IL23R) and IL-12Rbeta1 (IL12RB1), which is shared with the receptor for IL-12 (Parham et al., 2002). The receptor for IL-23 is constitutively associated with Jak2 (Janus kinase 2) and predominantly activates Stat3, with less Stat4 activation than IL-12.
Atlas Image
IL23A protein. The IL23A protein is composed of a signal peptide (light green) and a mature peptide (dark green) with four alpha-helices (dark yellow).

Description

The protein consists of 189 amino acids and is 20.7 kD, comprising a 19 amino acid signal peptide and a mature peptide (170 amino acids, 18.7 kD).

Expression

IL-23 is secreted by dendritic cells (DCs) and phagocytic cells activated with pathogens and pathogen-associated molecular patterns that act through toll-like receptors (TLRs) (Hunter, 2005; Kastelein et al., 2007; Goriely et al., 2008). The TLR2 ligand peptidoglycan, a cell wall component of Gram-positive bacteria, preferentially promotes the expression of IL23A but not IL12A through activation of a cytosolic receptor, nucleotide-binding oligomerization domain 2 (NOD2), with TLR2. Activation of the C-type lectins-Syc-CARD9 signaling pathway by the beta-glucan curdlan also induces IL-23 production by DCs (LeibundGut-Landmann et al., 2007). Prostaglandin E2 (PGE2) and ATP act on their G-protein-coupled receptors, EP2 and EP4 (PGE2) and P2Y (ATP), to enhance IL-23 production via an increase in cAMP concentration (Sheibanie et al., 2004; Yao et al., 2009; Schnurr et al., 2005). Lactic acid also facilitates IL-23 production (Shime et al., 2008). Although these factors themselves do not induce IL-23 production, they can shift the balance between IL-12 and IL-23 secretion by activated DCs or macrophages toward IL-23. Polarized Th1 and Th2 cells highly express IL23A mRNA but not IL12B mRNA (Oppmann et al., 2000). The roles of IL23A mRNA expression in T cells are unknown.

Function

IL-23 receptor is mainly expressed on activated/memory T cells and natural killer (NK) cells. Monocytes, macrophage and DCs also express IL-23 receptor at low levels (Parham et al., 2002). Although IL-23 does not directly stimulate the initial differentiation of naive T cells to Th17 cells, it is essential for the full differentiation of Th17 cells and promotes their expansion and maintenance to induce IL-17A production (Korn et al., 2009). NKT cells (Rachitskaya et al., 2008) and innate lymphoid cells such as lymphoid tissue induce (LTi)-like cells (Takatori et al., 2009; Buonocore et al., 2010) express IL-23 receptor and retinoic-acid-related orphan receptor (ROR) gammat and produce IL-17 in response to IL-23. IL-1beta and IL-23 also costimulate gammadelta T cells to induce IL-17 production without T cell receptor engagement (Sutton et al., 2009).

Homology

IL23A has homology with four-helix bundle cytokine family members such as IL12A (IL-12p35), IL-6, and G-CSF. IL23A and IL12A have the highest homology, with approximately 40% of sequence identity among this family.

Implicated in

Entity name
Various cancers
Note
Promotion of tumor incidence and growth
The expression of IL-23A mRNA is significantly elevated in various human cancers, such as melanoma, colon, ovarian, head and neck, lung, breast, and stomach cancers, when compared with adjacent normal tissues (Langowski et al., 2006). IL-23 upregulation is also observed in sera from multiple myeloma patients (Prabhala et al., 2010). A deficiency of IL23A promotes increased infiltration of cytotoxic T cells into the transformed tissue and mediates resistance to chemically induced tumors. IL-23 facilitates the induction of inflammation and angiogenesis in the tumor microenvironment and inhibits CD8+ T cells infiltration, thereby promoting tumor incidence and growth (Langowski et al., 2006; Langowski et al., 2007; Martin-Orozco and Dong, 2009). It has been suggested that IL-23 also suppresses carcinogenesis and metastasis in mouse models, where it acts independently of IL-17A (Teng et al., 2010). Stat3 signaling shifts the balance between IL-23 and IL-12 toward IL-23 in the tumor microenvironment (Kortylewski et al., 2009). In tumor-associated regulatory T cells, IL-23-activated Stat3 induces the upregulation of Foxp3 and IL-10.

Anti-tumor effects
In several mouse tumor models, IL-23 overexpression in tumors (Overwijk et al., 2006) or intratumoral injection of IL-23-introduced DCs (Hu et al., 2006) has been shown to induce tumoral infiltration of CD8+ T cells and to inhibit tumor growth. Systemic administration of IL-23 also suppresses the growth of a pre-existing tumor in mice (Kaiga et al., 2007).

Entity name
Ovarian cancer
Note
The occurrence of specific single nucleotide polymorphisms (SNPs) in the IL23R gene is increased in ovarian cancer patients compared with controls (dbSNPs: rs10889677) and in advanced ovarian cancer stage (dbSNPs: rs11465817) (Zhang et al., 2010).
Entity name
Inflammation and inflammatory diseases
Note
IL23A and IL23R knockout mice are resistant to the development of experimental autoimmune encephalomyelitis and collagen-induced arthritis (Hunter, 2005; Kastelein et al., 2007; Abraham and Cho, 2009; Korn et al., 2009). IL-23A deficiency or treatment with anti-IL-23A blocking antibodies suppresses intestinal inflammation induced in IL-10-deficient mice. Ubiquitous overexpression of IL-23A in mice results in multi-organ inflammation. Therefore, IL-23 upregulation is thought to promote many inflammatory and autoimmune diseases. Many SNPs in the IL23R gene are reported to be significantly associated with Crohns disease, ulcerative colitis, psoriasis, and ankylosing spondylitis. In particular, an uncommon allele at Arg381Gln (dbSNP: rs11209026) in the IL23R gene is associated with protection from Crohns diseases, ulcerative colitis, and psoriasis.
Entity name
T-cell-independent colitis
Note
IL-23 is involved in bacteria-driven innate immune colitis in Rag-/- mice. Recently, Buonocore et al. reported that IL-23 induces IL-17 and IFN-gamma expression by innate lymphoid cells expressing Thy-1, Stem cell antigen 1 (Sca-1), RORgammat and IL23R to mediate acute and chronic innate immune colitis (Buonocore et al., 2010).

Bibliography

Pubmed IDLast YearTitleAuthors
189760502009IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease.Abraham C et al
203934622010Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology.Buonocore S et al
180841852008How microorganisms tip the balance between interleukin-12 family members.Goriely S et al
169512062006Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells.Hu J et al
159990932005New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions.Hunter CA et al
175485922007Systemic administration of IL-23 induces potent antitumor immunity primarily mediated through Th1-type response in association with the endogenously expressed IL-12.Kaiga T et al
172911862007Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation.Kastelein RA et al
191329152009IL-17 and Th17 Cells.Korn T et al
191858462009Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment.Kortylewski M et al
173955382007Swords into plowshares: IL-23 repurposes tumor immune surveillance.Langowski JL et al
174501442007Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17.LeibundGut-Landmann S et al
195139432009The IL-17/IL-23 axis of inflammation in cancer: friend or foe?Martin-Orozco N et al
111143832000Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.Oppmann B et al
166219862006Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant.Overwijk WW et al
120233692002A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.Parham C et al
203954182010Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma.Prabhala RH et al
183906972008Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion.Rachitskaya AV et al
154860652005Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway.Schnurr M et al
151809652004Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells.Sheibanie AF et al
184907162008Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway.Shime H et al
196829292009Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity.Sutton CE et al
191146652009Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22.Takatori H et al
204041422010IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis.Teng MW et al
194659282009Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion.Yao C et al
200828502010Association of interleukin-23 receptor gene polymorphisms with risk of ovarian cancer.Zhang Z et al

Other Information

Locus ID:

NCBI: 51561
MIM: 605580
HGNC: 15488
Ensembl: ENSG00000110944

Variants:

dbSNP: 51561
ClinVar: 51561
TCGA: ENSG00000110944
COSMIC: IL23A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000110944ENST00000228534Q9NPF7

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Jak-STAT signaling pathwayKEGGko04630
Cytokine-cytokine receptor interactionKEGGhsa04060
Jak-STAT signaling pathwayKEGGhsa04630
Rheumatoid arthritisKEGGko05323
Rheumatoid arthritisKEGGhsa05323
TuberculosisKEGGko05152
TuberculosisKEGGhsa05152
PertussisKEGGko05133
PertussisKEGGhsa05133
Inflammatory bowel disease (IBD)KEGGhsa05321
Inflammatory bowel disease (IBD)KEGGko05321
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA166048654ustekinumabChemicalLabelAnnotationassociated

References

Pubmed IDYearTitleCitations
171870522007Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.548
191692542009Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.410
191692542009Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.410
215161112011The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF.403
172361322007A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.285
150707572004Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria.276
193222142009The IL-23/Th17 axis in the immunopathogenesis of psoriasis.240
166707652006The IL-23/IL-17 axis in inflammation.235
215763832011IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease.205
184978802008Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis.200

Citation

Norimitsu Inoue

IL23A (interleukin 23, alpha subunit p19)

Atlas Genet Cytogenet Oncol Haematol. 2010-05-01

Online version: http://atlasgeneticsoncology.org/gene/44517/il23a